Transdermal therapeutic system with high rate of utilization of active substance and dosing accuracy

ABSTRACT

A transdermal therapeutic system for administering at least one active pharmaceutical ingredient, including a polymer layer which is remote from the skin and is based on polyisobutylenes with a rate of application of at least 80 g/m 2 , and an adhesive skin-contact layer which is adjacent to the polymer layer remote from the skin and is based on acrylate copolymers with a rate of application of not more than 50 g/m 2 . The at least one active pharmaceutical ingredient is present in both the layer remote from the skin and the skin-contact layer.

The present application is a continuation of U.S. Parent applicationSer. No. 12/515,630 filed on May 20, 2009, the disclosure of which isincorporated herein by reference in its entirety, which claims priorityfrom PCT Patent Application No. PCT/EP07/09707 filed on Nov. 9, 2007,which claims priority from German Patent Application No. DE 10 2006 054733.0 filed on Nov. 21, 2006.

Transdermal therapeutic systems (ITS) have been introduced into therapyfor a number of years. For reference to the use in particular in thearea of pain therapy, reference is made to the literature (B. Asmussen,Transdermale Therapeutische System-Eigenschaften and Anwendungen; In:Likar, Rudolf: Praxis der transdermalen Schmerztherapie, 1^(st)edition-Bremen 2002).

A number of active ingredients have been introduced in recent years intotransdermal therapy in particular for highly active active ingredientswith daily doses below 30 mg, or even below 5 mg: nicotine, fentanyl,buprenorphine, nitroglycerin, estradiol, rotigotine, to mention just afew examples. Flat systems using at least one of the polymer groups ofsilicone polymers, polyisobutylene adhesive compositions or polyacrylateadhesive compositions have been used for all these substances. Becauseof the favorable opportunities of responding to the requirements ofactive ingredients through appropriate derivatization, and because theadhesion to the skin is generally sufficient without further additives,acrylate polymers are particularly preferably used for transdermaltherapeutic systems. Examples thereof are in particular the newlyintroduced Durogesic SMAT®, and numerous generic fentanyl TTS which werelaunched on the market in 2005 and 2006 by the companies Ratiopharm andHexal in Germany. However, other active ingredients have also preferablybeen made available on the human skin with the polymeric principle ofacrylic acid copolymer. Thus, transdermal therapeutic systems withnicotine (Nicotinel®-TTS), buprenorphine (Transtec®, Grünenthal) andestradiol (Estraderm MX®, Novartis) have successfully been launched onthe market.

System structures of such transdermal systems comprise one or morelayers, particular attention being paid in earlier years in particularto the aspect of the control of supply by the systems themselves.Typical structures in earlier times therefore provided a separation intoadhesive layer, membrane layer and reservoir layer, with the essentialproportion of active ingredient being present in the reservoir layer.

It is common to all these systems that it is frequently possible toadminister transdermally only a very small part of the active ingredientavailable, and thus the so-called system utilization rate is relativelylow This is particularly important for transdermal therapeutic systemswhich comprise costly active ingredients, especially novel syntheticactive ingredients such as rotigotine, fentanyl, buprenorphine orsufentanil.

The requirement to achieve a high rate of utilization of activeingredient is opposed by the requirement of a large layer thickness(application rate) of the adhesive layers and reservoir layers, which isnecessary for the adhesiveness and producibility, and by the property ofmost adhesive compositions of dissolving a large proportion of activeingredient before the high thermodynamic activity (close to thesaturation solubility) necessary for transdermal use is reached.

The requirement of large layer thicknesses together with high saturationsolubilities of the active ingredients in the polymers is the cause ofthe unfortunately undesirably large use of active ingredients in mosttransdermal therapeutic systems. Mention may be made by way of examplefor the prior art in the area of transdermal systems with restrictedutilization of active ingredients for example of U.S. Pat. No.5,240,711, which describes polyacrylate matrices with 0.1-20%buprenorphine base with addition of further constituents. U.S. Pat. No.6,090,405 describes transdermal systems for buprenorphine which comprisean acrylate copolymer and, contained therein, crosslinked acrylicpolymer particles. WO 03/018075 describes a transdermal therapeuticsystem with fentanyl or related substances as active ingredient, whichcomprises a matrix layer based on polyacrylate. On the grounds ofincreasing the rate of utilization of active ingredient, in this case acopolymer free of acrylic acid groups is selected because thesolubility, promoted by ion pair effects, of fentanyl and similar activeingredients is otherwise increased too greatly by carboxyl groups.

WO 03/097020 describes a two-layer system in which the layer on the skinside has a lower affinity for active ingredient than the layer remotefrom the skin and simultaneously has a larger layer thickness.

The objective according to the technical teaching of this publication isto achieve a constant delivery rate over lengthy periods of time. Alower rate of utilization due to active ingredient remaining in thelayer remote from the skin, which dissolves better, is thus certainlyfurther accepted.

EP 1 137 406 B1 describes a patch for transdermal administration ofvolatile active ingredients, especially nicotine. The patch has twolayers, the layer remote from the skin consisting of an activeingredient-containing silicone adhesive material, the skin-contact layerconsisting of an acrylic adhesive, and both layers having approximatelythe same thickness. It is pointed out that, after the lamination andreaching of an equilibrium, the acrylic adhesive layer likewise containspart of the active ingredient, specifically about 2.5 to 3.0% by weight.

Besides the economic factors described above, also very important areincreasingly restrictive requirements of the approval authorities forthe accuracy of dosage of transdermal therapeutic systems. Thus, coatingaccuracies with a standard deviation of about +/−5 g/m² can certainly beachieved with metering methods which can be carried out economically.With the weights per unit area which are customary in the art, of about50-100 g/m², accordingly the variations in the coating accuracy andlater the active ingredient content of the cut-out TTS are in the rangebetween 5 and 10%. This accuracy has certainly been sufficient inpharmaceutical approval procedures to date. However, with the 2005revision of the European Pharmacopoeia Monograph, accuracies with up toa standard deviation of below 3% are required if the median of the layerweight reached differs by up to 10% from the required value. Thisrequirement thus makes it no longer economically possible to coat withlayer thicknesses of about 50 g/m², e.g. according to the teaching of WO03/018075, a monolithic polyacrylate system with an active ingredientcontent of 5%, because the described system would be unlikely to receivepharmaceutical approval by the authorities in terms of the accuracy ofdosage.

On the other hand, the person skilled in the art prefers polymers whichdissolve well and adhere well for adhesion to the skin in order toimprove the acceptance and bioavailability of such systems. Polymersadhering to the skin which have emerged as ideal in recent years arepolyacrylates which, however, have the disadvantage of a high dissolvingcapacity for the active pharmaceutical ingredients which are normallysuitable for transdermal therapy.

It is therefore an object of the present invention to provide atransdermal therapeutic system with an acrylate copolymer skin-contactlayer, with a rate of active ingredient utilization which is improved bycomparison with the prior art, and with an accuracy of dosage which isincreased by comparison with the prior art.

The object is achieved according to the invention by providing atransdermal therapeutic system (TTS) comprising a backing layer which isessentially impermeable for the active ingredient, a layer which isremote from the skin and is based on polyisobutylenes, an adhesiveskin-contact layer based on acrylate copolymers which is thinner thanthe layer remote from the skin and, after production of the TTS,comprises the predominant part of the active ingredient, and adetachable protective layer which is essentially impermeable for theactive ingredient. The coating weight of the layer remote from the skinis according to the invention at least 80 g/m², preferably 100-200 g/m²;the coating weight of the skin-contact layer is according to theinvention not more than 50 g/m², preferably 20-30 g/m².

In a preferred embodiment, the ratio of the coating weight of the layerremote from the skin to that of the skin-contact layer is at least 2:1,particularly preferably from 3:1 to 5:1. Although the polyisobutyleneconnected as basis of the layer remote from the skin has a lowerdiffusibility than the polysiloxane used in the prior art, itsurprisingly emerges that the transdermal therapeutic system of theinvention is superior to the systems known in the prior art in terms ofthe rate of utilization of active ingredient and dosage accuracy.

The ITS Described Above can be Produced in the Following Way:

The active ingredient or the active ingredient mixture is dissolved in asuitable volatile solvent or in a mixture of such solvents, theresulting solution is mixed with the polymer composition which isintended for the layer remote from the skin and is based onpolyisobutylenes, and the resulting mixture is applied uniformly in alayer thickness of at least 200 μm (corresponding to 200 g/m²) to asuitable substrate, for example a siliconized plastic layer. Afterdrying and evaporation of the solvent contents, the activeingredient-containing polymer layer is covered with a further sheetwhich represents the later backing layer of the ITS of the invention.After removal of the plastic sheet serving as substrate, an activeingredient-free adhesive skin-contact layer based on acrylatecopolymers, and a detachable protective sheet is laminated onto theresulting laminate in such a way that the active ingredient-containinglayer remote from the skin and the adhesive skin-contact layer are incontact with one another. After the diffusion equalization which startsimmediately, most of the active ingredient(s) migrates out of thatremote from the skin into the skin-contact layer.

The invention described above makes it possible for the dosage of theactive ingredient or active ingredients to be very accurate andefficient through the introduction of the latter into the polymercomposition of polyisobutylenes which, on the one hand, is applied in arelatively large layer thickness and, on the other hand, exhibits a verylow dissolving capacity for the active ingredients used according to theinvention, and for the accuracy on coating a sheet with the activeingredient/polymer mixture to be very high because of the relativelygreat layer thickness. Further advantages emerge from the fact that theadhesive skin-contact layer based on acrylate copolymers need not becoated with the active ingredient(s), so that the thickness of thislayer is reduced below the coating weight of over 50 g/m², which iscustomary according to the previous prior art and is necessary foraccurate dosage, and preferably can even be restricted to a typical rateof application of 20-30 g/m².

A polyethylene terephthalate sheet optionally coated with apolyisobutylene, a polyacrylate or polysiloxane serves as backing layerwhich is essentially impermeable for the active ingredient(s).

The matrix layer (skin-contact layer) which is in contact with the skinconsists of acrylate copolymers. By this are meant copolymers ofmonomeric acrylic acid, methacrylic acid and/or suitable derivatives andoptionally monomeric vinyl compounds. The following monomers may bementioned by way of example: acrylic acid, methacrylic acid, acrylicesters and methacrylic esters, e.g. in particular n-butyl acrylate,n-butyl methacrylate, ethyl acrylate, 2-ethylhexyl acrylate, ethylmethacrylate, methyl acrylate, methyl methacrylate, tert-butyl acrylate,sec-butyl acrylate, tent-butyl methacrylate, cyclohexyl methacrylate,2-ethylhexyl methacrylate, isobornyl methacrylate, isobutylmethacrylate, isopropyl acrylate, isopropyl methacrylate and mixtures ofthese monomers. These monomers are esters of acrylic or methacrylic acidwhich have linear, branched or cyclic aliphatic C1-C12 substituents.These substituents may in turn be substituted for example by hydroxygroups. Esters which may be mentioned by way of example are2-hydroxyethyl methacrylate, 3-hydroxypropyl acrylate and3-hydroxypropyl methacrylate. Vinyl acetate may be mentioned as asuitable vinyl compound.

Active ingredients suitable for the purposes of the present inventionare in particular those which have high activity. The person skilled inthe art generally understands by this active ingredients whose dailydose is in the mg range, e.g. 1-500 mg. However, active ingredientspreferred according to the invention are those whose daily dose does notexceed 30 mg.

Suitable active ingredients for use in the TTS of the invention are forexample analgesics, bronchodilators, antidiabetics, vasodilators,anticraving agents and antiparkinson agents.

However, the TTS of the invention is particularly suitable for paintherapy, preferably with active ingredients from the group of opioids.This group of active pharmaceutical ingredients includes inter aliamorphine, heroin and further morphine derivatives; dihydromorphinederivatives such as hydromorphone (dihydrocodeine), oxycodone; morphinederivatives such as levorphanol, buprenorphine; analgesics of thepethidine group such as pethidine, ketobemidone, loperamide,diphenoxylate; methadone and derivatives such as levomethadone,dextromoramite, dextropropoxyphene; fentanyl and its derivative (e.g.alfentanil, sufentanil, remifentanil), benzomorphan derivatives such aspentazocine and phenylaminocyclohexynyl derivatives such as tilidine;tramadol. Particularly preferred for the treatment of breakthrough painare fast- and short-acting opioids such as morphine, tramadol, tilidine,oxycodone, hydromorphone, buprenorphine, fentanyl and levomethadone.

Further suitable examples from the group of analgesics are thefollowing: metamizole, phenazone, propyphenazone, flupirtine, nefopam,and from the group of antiepileptics are carbamazepine, gabapentine,clonazepam, also antidepressants such as amitryptiline.

The invention also includes the use of active ingredient combinationsconsisting of two or more medicinal substances, especially combinationsof the aforementioned analgesics.

The polymer layers, preferably the skin-contact layer of the ITS of theinvention, may further comprise various excipients or additives, forexample from the group of solubilizers, solvents, plasticizers,tackifiers, permeation improvers, pH regulators, antioxidants andpreservatives.

The Invention is Explained Below by Means of Examples: EXAMPLE 1

A solution of polyacrylic acid-co-2-ethylhexyl acrylate-co-vinylacetate, 30% (w/w) in ethyl acetate is coated in a layer thickness ofabout 65-70 μm onto a siliconized polyethylene terephthalate sheet (100μm thick) and dried in the open at 25° C. for 2 hours to result in anadhesive layer of 20 g/m². In a separate operation, 2 g of fentanylbase, 70 g of polyisobutylene 100, 28 g of polyisobutylene 10, 100 g ofmethyl ethyl ketone and 200 g of n-heptane are made into a viscoussolution and then stirred for 2 hours. This phase is coated with a layerthickness of about 500 onto a 15 μm thick sheet of polyethyleneterephthalate to result in an active ingredient-containing dry adhesivelayer of 100 g/m². This layer is laminated on the adhesive side with thepreviously fabricated acrylate copolymer layer (adhesive layer ontoadhesive layer) so that a continuous, two-layer matrix is produced.Detachment of the protective sheet produces an adhesive system which canbe stuck with the polyacrylate side onto the skin. The system can be cutto the required size by suitable cutting devices.

EXAMPLE 2

A solution of poly(2-ethylhexyl acrylate-co-vinylacetate-co-2-hydroxyethyl acrylate-co-2,3-epoxypropyl methacrylate), 30%(w/w) in ethyl acetate is coated in a layer thickness of about 65-70 μmonto a siliconized polyethylene terephthalate sheet (100 μm thick) anddried in the open at 25° C. for 2 hours to result in an adhesive layerof 20 g/m². In a separate operation, 1.5 g of fentanyl base, 70 g ofpolyisobutylene 100, 28 g of polyisobutylene 10, 100 g of methyl ethylketone and 200 g of n-heptane are made into a viscous solution and thenstirred for 2 hours. This phase is coated with a layer thickness ofabout 500 μm onto a 15 μm-thick sheet of polyethylene terephthalate toresult in an active ingredient-containing dry adhesive layer of 100g/m².

This layer is laminated on the adhesive side with the previouslyfabricated acrylate copolymer layer (adhesive layer onto adhesive layer)so that a continuous, two-layer matrix is produced. Detachment of theprotective sheet produces an adhesive system which can be stuck with thepolyacrylate side onto the skin. The system can be cut to the requiredsize by suitable cutting devices.

1. A transdermal therapeutic system comprising: at least one activepharmaceutical ingredient; a polymer layer which is remote from the skinand is based on polyisobutylenes; and an adhesive skin-contact layerwhich is adjacent to the polymer layer remote from the skin and is basedon acrylate copolymers; wherein a coating weight of the layer remotefrom the skin is at least 80 g/m² and a coating weight of theskin-contact layer is not more than 50 g/m²; and wherein the at leastone active pharmaceutical ingredient is present in both the layer remotefrom the skin and the skin-contact layer.
 2. The transdermal therapeuticsystem as claimed in claim 1; wherein the mass per area of the layerremote from the skin is 100-200 g/m².
 3. The transdermal therapeuticsystem as claimed in claim 1; wherein the mass per area of theskin-contact layer is 20-30 g/m².
 4. The transdermal therapeutic systemas claimed in claim 1; wherein the ratio of the mass per area of thelayer remote from the skin to that of the skin-contact layer is at least2:1.
 5. The transdermal therapeutic system as claimed in claim 4;wherein the ratio is from 3:1 to 5:1.
 6. The transdermal therapeuticsystem as claimed in claim 1; wherein, after production of the systemand diffusion equalization, a magority of the at least one activeingredient is located in the skin-contact layer.
 7. The transdermaltherapeutic system as claimed in claim 1; wherein the acrylatecopolymers of the skin-contact layer comprise at least one monomer unitselected from the group consisting of acrylic acid, methacrylic acid,acrylic esters, and methacrylic esters.
 8. The transdermal therapeuticsystem as claimed in claim 1; wherein the acrylate copolymers of theskin-contact layer additionally comprise vinyl acetate.
 9. Thetransdermal therapeutic system as claimed in claim 1; wherein the atleast one active ingredient is selected from the group of analgesics,bronchodilators, antidiabetics, vasodilators, anticraving agents, andantiparkinson agents.
 10. The transdermal therapeutic system as claimedin claim 9; wherein the at least one active ingredient is an analgesic.11. The transdermal therapeutic system as claimed in claim 10; whereinat least one of the active ingredients is an opioid.
 12. The transdermaltherapeutic system as claimed in claim 11; wherein the opioid isfentanyl and/or one of its derivatives.
 13. The transdermal therapeuticsystem as claimed in claim 12; wherein the fentanyl derivative isalfentanil, sufentanil, or remifentanil
 14. A process for producing atransdermal therapeutic system as claimed in claim 1, comprising: mixingthe at least one active ingredient, which is dissolved in a suitablevolatile solvent or solvent mixture, with the polymer composition whichis intended for the layer remote from the skin and is based onpolyisobutylenes; forming the the layer remote from the skin by:applying the resulting mixture uniformly in a layer thickness of atleast 200 μm to a siliconized plastic sheet; drying and evaporation ofthe solvent; and laminating the adhesive skin-contact layer onto thelayer remote from the skin in such a way that the activeingredient-containing layer remote from the skin and the adhesiveskin-contact layer are in contact with one another.
 15. The process asclaimed in claim 14; wherein the layer remote from the skin and theskin-contact layer are laminated together in such a way that migrationof the at least one active ingredient out of the former into the latteris made possible.
 16. The process as claimed in claim 14; wherein themass per area of the layer remote from the skin is 100-200 g/m² and themass per area of the skin-contact layer is 20-30 g/m².
 17. The processas claimed in claim 16; wherein the ratio of the mass per area of thelayer remote from the skin to that of the skin-contact layer is at least2:1.
 18. The process as claimed in claim 17; wherein the ratio is from3:1 to 5:1.
 19. The process as claimed in claim 14; wherein the at leastone active ingredient is fentanyl or a fentanyl derivative.
 20. Theprocess as claimed in claim 19; wherein the fentanyl derivative isalfentanil, sufentanil, or remifentanil.
 21. A transdermal therapeuticsystem for administering at least one active pharmaceutical ingredient,with a daily dose in a range of from 1 mg to 500 mg, comprising: apolymer layer which is remote from the skin and is based onpolyisobutylenes; and an adhesive skin-contact layer which is adjacentto the polymer layer remote from the skin and is based on acrylatecopolymers; wherein a mass per area of the layer remote from the skin isat least 80 g/m² and a mass per area of the skin-contact layer is notmore than 50 g/m²; and wherein the at least one active pharmaceuticalingredient is present in both the layer remote from the skin and theskin-contact layer.
 22. A transdermal therapeutic system foradministering at least one active pharmaceutical ingredient, with adaily dose not exceeding 30 mg, comprising: a polymer layer which isremote from the skin and is based on polyisobutylenes; and an adhesiveskin-contact layer which is adjacent to the polymer layer remote fromthe skin and is based on acrylate copolymers; wherein a coating weightof the layer remote from the skin is at least 80 g/m² and a coatingweight of the skin-contact layer is not more than 50 g/m²; and whereinthe at least one active pharmaceutical ingredient is present in both thelayer remote from the skin and the skin-contact layer.